Precision medicine in Non-Small Cell Lung Cancer, with a focus on KRAS mutations

Abstract

Precision medicine in Non-Small Cell Lung Cancer, with a focus on KRAS mutations Ella Äng Eklund Avdelningen för kirurgi, Institutionen för kliniska vetenskaper, Sahlgrenska akademin, Göteborgs universitet, Sverige, 2025 Abstract KRAS mutations - the most common oncogenic drivers in Non-Small Cell Lung Cancer (NSCLC) accounting for around 35% of patients - were historically linked to poor prognosis. With immune checkpoint blockade (ICB), this may be changing. There is a need to clarify the prognostic and predictive roles of KRAS and discover ICB response biomarkers to refine treatment and develop new therapies for KRAS-mutant NSCLC. The aim of this thesis was to broadly investigate the overall prognostic and predictive impact of KRAS mutations on currently available treatments, explore new prognostic biomarkers for ICB treatment, study the impact of aging on KRAS mutated lung cancer progression and explore novel treatment vulnerabilities. Our findings from multicenter retrospective studies show that having KRAS mutations is a negative prognostic factor overall and for chemotherapy treatment in the metastatic setting (stage IV). However, having a KRAS mutation and a high (≥50%) PD-L1 expression is a positive prognostic factor for ICB monotherapy. We have also elucidated that all KRAS mutations are not the same, as KRAS G12D seems to respond less well than KRAS G12C or G12V to ICB. In locally advanced (stage III) NSCLC treated with combined chemoradiotherapy, the negative prognostic impact of KRAS mutations can be reversed with the implementation of adjuvant ICB treatment. In contrast to stage III and stage IV disease we found that in early-stage resectable NSCLC (stage I-II), KRAS status – alone or combined with tumor size – did not affect overall survival. In the prospectively included BIOLUNG cohort we identified KRAS+LRP1B mutation (and KRAS+LRP1B+TP53) as a potential predictive biomarker for ICB benefit. Finally, aging epigenetically induces ATF4 in KRAS mutated adenocarcinoma, driving EMT, anoikis resistance, and glutamine-dependent metabolic plasticity for metastasis in preclinical models, and higher ATF4 correlated with advanced stage and poorer survival in patients. This finding has identified new potential therapeutic targets. In conclusion, findings in this thesis add to the understanding of the prognostic and predictive impact of KRAS mutations and that it is context-dependent. Potential new predictive biomarkers for ICB treatment have been identified and provided important biological insight including identifying novel therapeutic targets. Keywords: Non-Small Cell Lung Cancer, KRAS-mutations, precision medicine